Deficiency for the cysteine protease cathepsin L impairs Myc-induced tumorigenesis in a mouse model of pancreatic neuroendocrine cancer.

Abstract

Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycERTAM;Bcl-xL model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L in Myc-induced tumor progression. By employing a cysteine cathepsin activity probe in vivo and in vitro, we first established that cathepsin activity increases during the initial stages of MycERTAM;Bcl-xL tumor development. Among the cathepsin family members investigated, only cathepsin L was predominately produced by beta-tumor cells in neoplastic pancreata and, consistent with this, cathepsin L mRNA expression was rapidly upregulated following Myc activation in the beta cell compartment. By contrast, cathepsins B, S and C were highly enriched in tumor-infiltrating leukocytes. Genetic deletion of cathepsin L had no discernible effect on the initiation of neoplastic growth or concordant angiogenesis. However, the tumors that developed in the cathepsin L-deficient background were markedly reduced in size relative to their typical wild-type counterparts, indicative of a role for cathepsin L in enabling expansive tumor growth. Thus, genetic blockade of cathepsin L activity is inferred to retard Myc-driven tumor growth, encouraging the potential utility of pharmacological inhibitors of cysteine cathepsins in treating late stage tumors.

• Authors: Nicola R Brindle, Johanna A Joyce, Fanya Rostker, Elizabeth R Lawlor, Lamorna Swigart-Brown, Gerard Evan, Douglas Hanahan, Ksenya Shchors
• Journal: PloS one (PLoS One) Vol. 10 Issue 4 Pg. e0120348 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25927437 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Myc protein, mouse
• Proto-Oncogene Proteins c-myc
• bcl-X Protein
• Cathepsin L
• Ctsl protein, mouse

Topics

• Animals
• Cathepsin L (deficiency)
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Leukocytes (metabolism, pathology)
• Mice
• Mice, Transgenic
• Neoplasms, Experimental (genetics, metabolism, pathology)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• bcl-X Protein (genetics, metabolism)